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1.
Int J Med Mushrooms ; 23(6): 1-11, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34369729

RESUMO

Neuritin is important in neuritogenesis, neurite arborization, and neurite extension. Lignosus rhinocerotis sclerotia extracts and nerve growth factor (NGF) have been well documented to possess positive neurite stimulatory effects. However, the correlation of neuritin expression with neurite outgrowth of L. rhinocerotis and NGF cotreatment of PC12 cells remains unknown. Thus, the present study investigated neuritin expression in PC12 cells treated with 5 ng/mL of NGF and L. rhinocerotis extracts (20-1280 µg/mL) concurrently for 48 h. The neurite outgrowth score was quantitated, and total protein was harvested for enzyme-linked immunosorbent assay. There was a significant difference (P = 0.051) in neuritin protein abundance in 640 µg/mL of L. rhinocerotis aqueous cotreatment with 5 ng/mL of NGF-treated cells (5 ± 0.39 ng/mL) and 50 ng/mL of NGF-treated PC12 cells (5 ± 0.48 ng/mL) compared to untreated cells (1.9 ± 0.65 ng/ mL), with an average neurite length of 98 ± 3.66, 106 ± 3.00, and 73 ± 4.79 µm, respectively. Expression of microtubule element ß3 tubulin was increased in PC12 cells treated with 50 ng/mL of NGF (3.5 ± 0.21-fold) and also cells cotreated with 640 µg/mL of extract and 5 ng/mL of NGF (4.9 ± 0.29-fold) compared to untreated cells. Upregulation of ß3 tubulin expression in this study confirmed the elongation of PC12 cell processes. Correlation analysis showed that neuritin protein abundance is positively proportional to the average neurite length in PC12 cells cotreated with L. rhinocerotis extract and 5 ng/mL of NGF. This study highlights that neuritin modulation is involved in neurite outgrowth induced by L. rhinocerotis treatment. To our knowledge, this is the first report to show that tiger milk mushroom extracts induce neuritin expression.


Assuntos
Agaricales , Animais , Fator de Crescimento Neural/farmacologia , Neuritos , Crescimento Neuronal , Células PC12 , Polyporaceae , Ratos
2.
Sci Rep ; 11(1): 13873, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230516

RESUMO

The neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (rs = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (rs = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (rs = - 0.659, P = 0.013), and in combination with NGF (rs = - 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.


Assuntos
Ácido Glutâmico/farmacologia , Voluntários Saudáveis , Injeções , Músculo Masseter/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Caracteres Sexuais , Adulto , Biomarcadores/metabolismo , Tecido Conjuntivo/metabolismo , Feminino , Humanos , Masculino , Mastigação , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Dor/patologia , Limiar da Dor/efeitos dos fármacos , Pressão , Receptores de N-Metil-D-Aspartato/metabolismo , Substância P/metabolismo , Fatores de Tempo
3.
Pharmacology ; 106(7-8): 390-399, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33979803

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain characterized by degeneration of cholinergic neurons which is directly linked to cognitive decline. Nerve growth factor (NGF) is the most potent protective factor for cholinergic neurons, additionally the NMDA antagonist memantine blocks glutamate-mediated excitotoxic activity. Quinidine is an inhibitor of organic cation transporter 2 (OCT2). OCT2 is located on cholinergic neurons and plays a role in presynaptic reuptake and recycling of acetylcholine in the brain. We hypothesize that quinidine can modulate the protective effects of NGF and memantine on cholinergic neurons in organotypic brain slices of the nucleus basalis of Meynert (nBM). METHODS: Organotypic brain slices of nBM were incubated with 100 ng/mL NGF, 10 µM memantine, 10 µM quinidine, and combinations of these treatments for 2 weeks. Cholinergic neurons were immunohistochemically stained for choline acetyltransferase (ChAT). RESULTS: Our data show that NGF as well as memantine counteracted the cell death of cholinergic nBM neurons. Quinidine alone had no toxic effect on cholinergic neurons but inhibited the protective effect of NGF and memantine when applied simultaneously. DISCUSSION/CONCLUSION: Our data provide evidence that quinidine modulates the survival of cholinergic nBM neurons via OCT2.


Assuntos
Memantina/farmacologia , Fator de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/farmacologia , Quinidina/farmacologia , Acetilcolina/metabolismo , Animais , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Neurônios Colinérgicos , Camundongos , Camundongos Endogâmicos C57BL , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Técnicas de Cultura de Tecidos
4.
Chem Biol Interact ; 341: 109454, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-33798505

RESUMO

Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.


Assuntos
Antibacterianos/farmacologia , Doxiciclina/farmacologia , Fator de Crescimento Neural/metabolismo , Animais , Carbazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Proteína GAP-43/metabolismo , Alcaloides Indólicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Proteínas de Neurofilamentos/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapsinas/metabolismo
5.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806699

RESUMO

Nociceptors sense hazards via plasmalemmal cation channels, including transient receptor potential vanilloid 1 (TRPV1). Nerve growth factor (NGF) sensitises TRPV1 to capsaicin (CAPS), modulates nociceptor excitability and induces thermal hyperalgesia, but cellular mechanisms remain unclear. Confocal microscopy was used to image changes in intracellular Ca2+ concentration ([Ca2+]i) across neuronal populations in dorsal root ganglia (DRG) explants from pirt-GCaMP3 adult mice, which express a fluorescent reporter in their sensory neurons. Raised [Ca2+]i was detected in 84 neurons of three DRG explants exposed to NGF (100 ng/mL) and most (96%) of these were also excited by 1 µM CAPS. NGF elevated [Ca2+]i in about one-third of the neurons stimulated by 1 µM CAPS, whether applied before or after the latter. In neurons excitable by NGF, CAPS-evoked [Ca2+]i signals appeared significantly sooner (e.g., respective lags of 1.0 ± 0.1 and 1.9 ± 0.1 min), were much (>30%) brighter and lasted longer (6.6 ± 0.4 vs. 3.9 ± 0.2 min) relative to those non-responsive to the neurotrophin. CAPS tachyphylaxis lowered signal intensity by ~60% but was largely prevented by NGF. Increasing CAPS from 1 to 10 µM nearly doubled the number of cells activated but only modestly increased the amount co-activated by NGF. In conclusion, a sub-population of the CAPS-sensitive neurons in adult mouse DRG that can be excited by NGF is more sensitive to CAPS, responds with stronger signals and is further sensitised by transient exposure to the neurotrophin.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Capsaicina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Animais , Feminino , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Masculino , Camundongos , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Nociceptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo
6.
Biochem Biophys Res Commun ; 557: 174-179, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33865226

RESUMO

Involvement of the bone matrix protein osteocalcin (OC) in the development of learning and memory, and the prevention of anxiety-like behaviors in mice. However, the direct effects of OC on neurons are still unknown comparing to the mechanism how OC affects systemic energy expenditure and glucose homeostasis. In this study, we investigated the effect of OC on proliferation, differentiation, and survival of neurons using the rat pheochromocytoma cell line PC12. RT-PCR analysis for OC receptor candidates revealed that Gpr158, but not Gprc6a, mRNA was expressed in PC12 cells. The growth of PC12 cells cultured in the presence of 5-50 ng/mL of either uncarboxylated (GluOC) or carboxylated (GlaOC) OC was increased compared to cells cultured in the absence of OC. In addition, NGF-induced neurite outgrowth was enhanced by OC, and H2O2-induced cell death was suppressed by pretreatment with OC. All of these results were observed for both GluOC and GlaOC at comparable levels, suggesting that OC may directly affect cell proliferation, differentiation, and survival by binding to its candidate receptor, GPR158.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Osteocalcina/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Peróxido de Hidrogênio/toxicidade , Fator de Crescimento Neural/farmacologia , Neuritos/efeitos dos fármacos , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismo , Células PC12 , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
7.
Angew Chem Int Ed Engl ; 60(22): 12319-12322, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-33770418

RESUMO

We herein develop a concentration gradient generator (CGG) on a microfluidic chip for diluting different nanoparticles. Specifically designed compact disk (CD)-shaped microchannels in the CGG module could thoroughly mix the flowing solutions and generate a linear concentration gradient of nanoparticles without aggregation. We combine the CGG with a single-cell trapper array (SCA) on microfluidics to evaluate the concentration-dependent bioeffects of the nanoparticles. The precise control of the spatiotemporal generation of nanoparticle concentration on the CGG module and the single-cell-level monitoring of the cell behaviors on the SCA module by a high-content system in real time, render the CGG-SCA system a highly precise platform, which can exclude the average effect of cell population and reflect the response of individual cells to the gradient concentrations accurately. In addition, the CGG-SCA system provides an automated platform for high-throughput screening of nanomedicines with high precision and low sample consumption.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Nanopartículas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Lipídeos/química , Microfluídica , Fator de Crescimento Neural/química , Fator de Crescimento Neural/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Análise de Célula Única
8.
J Endod ; 47(6): 924-931, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33652017

RESUMO

INTRODUCTION: The goal of regenerative endodontic procedures is to preserve and stimulate stem cells from the apical papilla (SCAPs) to develop the pulp-dentin complex using various growth factors and scaffolds. We hypothesized that the treatment of SCAPs with vascular endothelial growth factor (VEGF) or nerve growth factor (NGF) may impact the expression of osteogenic and dentinogenic markers. METHODS: The optimum concentration of VEGF and NGF on SCAP viability was assessed and introduced to SCAPs for 6-24 hours. SCAPs were also challenged with Escherichia coli lipopolysaccharide (LPS). Messenger RNA (mRNA) expression of DSPP, DMP1, TGFB1, OCN, SP7, and TWIST1 was examined via quantitative reverse transcription polymerase chain reaction. Immunohistochemistry was used to verify protein expression. In addition, total RNA from NGF-treated SCAPs in the presence or absence of LPS was extracted for RNA sequencing. RESULTS: Compared with untreated cells, NGF-treated SCAPs showed markedly higher levels of DSPP, DMP1, and TGFB1 mRNAs (>9-fold change, P < .05), and SCAPs treated with both VEGF and NGF showed a significant increase of DSPP and TGFB1 mRNAs (P < .05). In addition, in LPS-challenged SCAPs, treatment with these growth factors also exhibited increased expression of DSPP, DMP1, and TGFB1 mRNAs, with the most significant change induced by VEGF (P < .05). Immunohistochemistry confirmed increased dentin sialophosphoprotein, dentin matrix acidic phosphoprotein 1, and transforming growth factor beta 1 protein expression in treated SCAPs. RNA sequencing revealed multiple pathways regulated by NGF, including TGF-ß and neurogenic pathways. CONCLUSIONS: VEGF- and NGF-induced dentinogenic/neuronal/healing marker expression in SCAPs indicates the potential value of applying these growth factors in regenerative endodontic procedures.


Assuntos
Papila Dentária , Fator A de Crescimento do Endotélio Vascular , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Fator de Crescimento Neural/farmacologia , Osteogênese , Células-Tronco
9.
Biochem Biophys Res Commun ; 549: 98-104, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33667715

RESUMO

The ßγ subunit of heterotrimeric G proteins, a key molecule in the G protein-coupled receptors (GPCRs) signaling pathway, has been shown to be an important factor in the modulation of the microtubule cytoskeleton. Gßγ has been shown to bind to tubulin, stimulate microtubule assembly, and promote neurite outgrowth of PC12 cells. In this study, we demonstrate that in addition to microtubules, Gßγ also interacts with actin filaments, and this interaction increases during NGF-induced neuronal differentiation of PC12 cells. We further demonstrate that the Gßγ-actin interaction occurs independently of microtubules as nocodazole, a well-known microtubule depolymerizing agent did not inhibit Gßγ-actin complex formation in PC12 cells. A confocal microscopic analysis of NGF-treated PC12 cells revealed that Gßγ co-localizes with both actin and microtubule cytoskeleton along neurites, with specific co-localization of Gßγ with actin at the distal end of these neuronal processes. Furthermore, we show that Gßγ interacts with the actin cytoskeleton in primary hippocampal and cerebellar rat neurons. Our results indicate that Gßγ serves as an important modulator of the neuronal cytoskeleton by interacting with both microtubules and actin filaments, and is likely to participate in various aspects of neuronal differentiation including axon and growth cone formation.


Assuntos
Citoesqueleto de Actina/metabolismo , Diferenciação Celular , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Actinas/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Diferenciação Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Hipocampo/citologia , Modelos Biológicos , Fator de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Células PC12 , Polimerização/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
10.
Neurotox Res ; 39(3): 886-896, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33666886

RESUMO

Carvacrol (CARV) is a phytochemical widely used as flavoring, preservative, and fragrance in food and cosmetic industries. CARV is able to cross the blood-brain barrier (BBB) and has demonstrated protective potential against neurodegenerative diseases by several mechanisms, including antioxidant, anti-inflammatory, anticholinesterase, and antiapoptotic effects. However, it is not known whether CARV is able to modulate axonal and synaptic plasticity, crucial events in cognition, memory, and learning. Abnormalities in axonal and synaptic plasticity, low levels of neurotrophins, and bioenergetic failure have been associated with the pathogenesis of neurodegenerative diseases, including Parkinson's (PD) and Alzheimer's diseases (ADs). Small lipophilic molecules with neurotrophic activity might be able to restore the axonal and synaptic networks that are lost in neurodegenerative processes. Therefore, this study investigated the neurotrophic potential of CARV in PC12 cell-based neuronal model. Carvacrol induced neurite outgrowth by activating the NGF high-affinity trkA receptor and the downstream PI3K-AKT and MAPK-ERK pathways, without depending on NGF. In addition, CARV increased the expression of proteins involved in neuronal plasticity (ß-tubulin III, F-actin, 200-kDa neurofilament, GAP-43 and synapsin-I) and improved bioenergetics (AMPKα, p-AMPKα, and ATP). Our study showed, for the first time, a promising neurotrophic mechanism of CARV that could be beneficial in neurodegenerative and neurological diseases.


Assuntos
Axônios/efeitos dos fármacos , Cimenos/farmacologia , Fatores de Crescimento Neural/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Axônios/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Fator de Crescimento Neural/farmacologia , Regeneração Nervosa/fisiologia , Células PC12 , Ratos , Sinapses/fisiologia
11.
Bioorg Med Chem Lett ; 36: 127832, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33524533

RESUMO

Natural products (NPs) are very important sources for the development of new drugs. Merrillianone and cycloparvifloralone, isolated from the roots, stems, and fruits of Illicium henryi Diels, are two natural sesquiterpene compounds. In continuation of our effort to discovery more effective neurotrophic compounds from NPs, a series of novel merrillianone/cycloparviforalone based esters 2a-i, 3a-g and 3i-q were prepared and their structures were characterized by 1H NMR, 13C NMR and IR spectral analyses. Furthermore, the spatial structure of compound 2h was unambiguously confirmed by X-ray crystallography. The neurite outgrowth-promoting activity results indicated that most of the target derivatives exhibited more potent neurite outgrowth-promoting activity than merrillianone and cycloparviforalone. Among all target derivatives, the neurite outgrowth-promoting activity of compounds 2a, 3a and 3b was about 2-fold stronger than that of their precursors merrillianone and cycloparviforalone, respectively. Besides, compounds 2a and 3a displayed relatively low cytotoxicity to normal GES-1 cells. Moreover, these derivatives had good hydrolytic stability. Finally, some interesting results of the structure-activity relationships (SARs) were also discussed. This work will pave the way for the development of merrillianone/cycloparviforalone derivatives as potential neurotrophic agents.


Assuntos
Descoberta de Drogas , Ésteres/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ésteres/química , Ésteres/isolamento & purificação , Humanos , Illicium/química , Modelos Moleculares , Conformação Molecular , Fator de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
12.
Biosci Biotechnol Biochem ; 85(3): 675-686, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33589896

RESUMO

Gangliosides (GLSs) are ubiquitously distributed in all tissues but highly enriched in nervous system. Currently, it is unclear how exogenous GLSs regulate neuritogenesis, although neural functions of endogenous GLSs are widely studied. Herein, we evaluated the neuritogenic activities and mechanism of sea urchin gangliosides (SU-GLSs) in vitro. These different glycosylated SU-GLSs, including GM4(1S), GD4(1S), GD4(2A), and GD4(2G), promoted differentiation of NGF-induced PC12 cells in a dose-dependent and structure-selective manner. Sulfate-type and disialo-type GLSs exhibited stronger neuritogenic effects than monosialoganglioside GM1. Furthermore, SU-GLSs might act as neurotrophic factors possessing neuritogenic effects, via targeting tyrosine-kinase receptors (TrkA and TrkB) and activating MEK1/2-ERK1/2-CREB and PI3K-Akt-CREB pathways. This activation resulted in increased expression and secretion of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). These pathways were verified by specific inhibitors. Our results confirmed the neuritogenic functions of SU-GLS in vitro and indicated their potential roles as natural nutrition for neuritogenesis.


Assuntos
Gangliosídeos/farmacologia , Neuritos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Ouriços-do-Mar/química , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Diferenciação Celular/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Neurônios/citologia , Neurônios/metabolismo , Células PC12 , Proteínas Quinases/metabolismo , Ratos
13.
Eur Rev Med Pharmacol Sci ; 25(1): 215-221, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33506910

RESUMO

OBJECTIVE: To investigate the clinical efficacy of combination of mouse nerve growth factor (NGF) and nimodipine in the treatment of neonatal intracranial hemorrhage (NICH) and its effect on plasma platelet-activating factor (PAF), C-type natriuretic peptide (CNP), matrix metalloproteinase-2 (MMP-2), and neurological function. PATIENTS AND METHODS: A total of 90 infants with severe ICH admitted to our hospital from December 2016 to December 2018 were enrolled for retrospective study. According to different treatment schemes, they were assigned into 2 groups: group A (n=40) treated with mouse NGF plus nimodipine; group B (n=50) treated with nimodipine. The recovery time, serum indexes (PAF, MMP-2, CNP), neurological function (neonatal behavioral neurological assessment (NBNA) score), complications, and total effective rate of patients were recorded, and the satisfaction degree of family members was statistically analyzed. RESULTS: Patients in group A showed shorter recovery time, down-regulated PAF and MMP-2, evidently up-regulated CNP, and significantly increased NBNA score after one/two weeks of treatment, as well as fewer complications, higher total effective rate and higher satisfaction of family members. CONCLUSIONS: To sum up, the combination of mouse NGF and nimodipine achieves good clinical efficacy in NICH, which down-regulates plasma PAF and MMP-2, up-regulates CNP, and improves neurological function. Therefore, it is suitable for clinical promotion.


Assuntos
Doenças do Recém-Nascido/tratamento farmacológico , Hemorragias Intracranianas/tratamento farmacológico , Fator de Crescimento Neural/farmacologia , Nimodipina/farmacologia , Animais , Humanos , Recém-Nascido , Doenças do Recém-Nascido/sangue , Injeções Intramusculares , Hemorragias Intracranianas/sangue , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Peptídeo Natriurético Tipo C/sangue , Peptídeo Natriurético Tipo C/metabolismo , Fator de Crescimento Neural/administração & dosagem , Nimodipina/administração & dosagem , Fator de Ativação de Plaquetas/metabolismo , Estudos Retrospectivos
14.
J Orthop Surg Res ; 16(1): 74, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478541

RESUMO

BACKGROUND: Mandibular fracture healing is a complex process involving nerves and growth factors. Nerve growth factor (NGF) not only facilitates the maintenance of sympathetic neurite growth but also stimulates other growth factors that can promote the essential osteogenesis and angiogenesis for fracture healing. Therefore, it is necessary to analyze the combined effects of NGF, bone morphogenic protein-9 (BMP-9), and vascular endothelial growth factor (VEGF) to accelerate the healing of mandible fractures. METHODS: The models of mandible fracture with local nerve injury established in 48 rabbits were randomly divided into nerve growth factor group (NGF group), gelatin sponge group (GS group), blank group, and intact group. The recovery of nerve reflex was assessed by observing the number of rabbits with lower lip responses to acupuncture. The fracture healing was observed with visual and CBCT, and then callus tissues from the mandibular fracture area were collected for hematoxylin and eosin (HE) staining observation, and the expression of BMP-9 and VEGF in callus at different stages was detected by quantitative real-time PCR (qRT-PCR). RESULTS: Needling reaction in the lower lip showed the number of animals with nerve reflex recovery was significantly higher in the NGF group than that in the GS and blank groups at the 2nd and 4th weeks after the operation. The combined results of macroscopic observation, CBCT examination, and histological analysis showed that a large number of osteoblasts and some vascular endothelial cells were found around the trabecular bone in the NGF group and the amount of callus formation and reconstruction was better than that in the GS group at the 2nd week after the operation. The qRT-PCR results indicated that the expression levels of BMP-9 and VEGF in the four groups reached the highest values at the 2nd week, while the expression levels of both in the NGF group were significantly higher than that in the GS group. CONCLUSION: The exogenous NGF could accelerate the healing of mandible fractures. This work will provide a new foundation and theoretical basis for clarifying the mechanism of fracture healing, thereby promoting fracture healing and reducing the disability rate of patients.


Assuntos
Consolidação da Fratura/genética , Expressão Gênica/efeitos dos fármacos , Fator 2 de Diferenciação de Crescimento/genética , Fator 2 de Diferenciação de Crescimento/metabolismo , Mandíbula/inervação , Traumatismos Mandibulares/genética , Traumatismos Mandibulares/fisiopatologia , Fator de Crescimento Neural/farmacologia , Traumatismos dos Nervos Periféricos/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Consolidação da Fratura/fisiologia , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Coelhos , Estimulação Química
15.
J Orthop Surg Res ; 16(1): 51, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33436038

RESUMO

BACKGROUND: Osseointegration is the premise of the chewing function of dental implant. Nerve growth factor (NGF), as a neurotrophic factor, can induce bone healing. However, the influence of NGF-chondroitin sulfate (CS)/hydroxyapatite (HA)-coating composite implant on the osseointegration and innervations is still not entirely clear. MATERIALS AND METHODS: NGF-CS/HA-coating composite implants were prepared using the modified biomimetic method. The characteristics of NGF-CS/HA-coating implants were determined using a scanning electron microscope. After NGF-CS/HA-coating implants were placed in the mandible of Beagle dogs, the early osseointegration and innervation in peri-implant tissues were assessed through X-ray, Micro-CT, maximal pull-out force, double fluorescence staining, toluidine blue staining, DiI neural tracer, immunohistochemistry, and RT-qPCR assays. RESULTS: NGF-CS/HA-coating composite implants were made successfully, which presented porous mesh structures with the main components (Ti and HA). Besides, we revealed that implantation of NGF-CS/HA-coating implants significantly changed the morphology of bone tissues and elevated maximum output, MAR, BIC, and nerve fiber in the mandible of Beagle dogs. Moreover, we proved that the implantation of NGF-CS/HA-coating implants also markedly upregulated the levels of NGF, osteogenesis differentiation, and neurogenic differentiation-related genes in the mandible of Beagle dogs. CONCLUSION: Implantation of NGF-CS/HA-coating composite implants has significant induction effects on the early osseointegration and nerve regeneration of peri-implant tissues in the mandible of Beagle dogs.


Assuntos
Sulfatos de Condroitina/administração & dosagem , Sulfatos de Condroitina/farmacologia , Resinas Compostas , Implantes Dentários , Planejamento de Prótese Dentária , Mandíbula/inervação , Mandíbula/fisiologia , Células-Tronco Mesenquimais/fisiologia , Fator de Crescimento Neural/administração & dosagem , Fator de Crescimento Neural/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Osseointegração/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Cães , Masculino , Mandíbula/metabolismo , Fator de Crescimento Neural/metabolismo , Regeneração Nervosa/fisiologia , Osseointegração/fisiologia , Cicatrização
16.
Sci Rep ; 11(1): 1672, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462282

RESUMO

We previously described the profibrogenic effect of NGF on conjunctival Fibroblasts (FBs) and its ability to trigger apoptosis in TGFß1-induced myofibroblasts (myoFBs). Herein, cell apoptosis/signalling, cytokines' signature in conditioned media and inflammatory as well as angiogenic pathway were investigated. Experimental myoFBs were exposed to NGF (0.1-100 ng/mL), at defined time-point for confocal and biomolecular analysis. Cells were analysed for apoptotic and cell signalling activation in cell extracts and for some inflammatory and proinflammatory/angiogenic factors' activations. NGF triggered cJun overexpression and phospho-p65-NFkB nuclear translocation. A decreased Bcl2:Bax ratio and a significant expression of smad7 were confirmed in early AnnexinV-positive myoFBs. A specific protein signature characterised the conditioned media: a dose dependent decrease occurred for IL8, IL6 while a selective increase was observed for VEGF and cyr61 (protein/mRNA). TIMP1 levels were unaffected. Herein, NGF modulation of smad7, the specific IL8 and IL6 as well as VEGF and cyr61 modulation deserve more attention as opening to alternative approaches to counteract fibrosis.


Assuntos
Túnica Conjuntiva/patologia , Miofibroblastos/patologia , Fator de Crescimento Neural/farmacologia , Fator de Crescimento Transformador beta1/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células Cultivadas , Túnica Conjuntiva/efeitos dos fármacos , Túnica Conjuntiva/metabolismo , Fibrose , Humanos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Transdução de Sinais
17.
Mol Neurobiol ; 58(3): 964-982, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33063281

RESUMO

At present, chronic post-surgical pain (CPSP) is difficult to prevent and cure clinically because of our lack of understanding of its mechanisms. Surgical injury induces the upregulation of voltage-gated sodium channel Nav1.7 in dorsal root ganglion (DRG) neurons, suggesting that Nav1.7 is involved in the development of CPSP. However, the mechanism leading to persistent dysregulation of Nav1.7 is largely unknown. Given that nerve growth factor (NGF) induces a long-term increase in the neuronal hyperexcitability after injury, we hypothesized that NGF might cause the long-term dysregulation of Nav1.7. In this study, we aimed to investigate whether Nav1.7 regulation by NGF is involved in CPSP and thus contributes to the specific mechanisms involved in the development of CPSP. Using conditional nociceptor-specific Nav1.7 knockout mice, we confirmed the involvement of Nav1.7 in NGF-induced pain and identified its role in the maintenance of pain behavior during long-term observations (up to 14 days). Using western blot analyses and immunostaining, we showed that NGF could trigger the upregulation of Nav1.7 expression and thus support the development of CPSP in rats. Using pharmacological approaches, we showed that the increase of Nav1.7 might be partly regulated by an NGF/TrkA-SGK1-Nedd4-2-mediated pathway. Furthermore, reversing the upregulation of Nav1.7 in DRG could alleviate spinal sensitization. Our results suggest that the maintained upregulation of Nav1.7 triggered by NGF contributes to the development of CPSP. Attenuating the dysregulation of Nav1.7 in peripheral nociceptors may be a strategy to prevent the transition from acute post-surgical pain to CPSP.


Assuntos
Proteínas Imediatamente Precoces/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Fator de Crescimento Neural/farmacologia , Dor Pós-Operatória/genética , Proteínas Serina-Treonina Quinases/metabolismo , Regulação para Cima , Analgésicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hidrazinas/farmacologia , Proteínas Imediatamente Precoces/antagonistas & inibidores , Indóis/farmacologia , Masculino , Camundongos Knockout , Modelos Biológicos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor Pós-Operatória/patologia , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ratos Sprague-Dawley , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Medula Espinal/patologia , Ubiquitinação/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
18.
Nat Prod Res ; 35(5): 757-762, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31030559

RESUMO

Two new sesquiterpenoids, including a kessane-type sesquiterpenoid (1) and one bisabolane derivative (2), together with fourteen known sesquiterpenoids (3-16), were isolated from the roots and rhizomes of Valeriana amurensis. The structures of new compounds were established on the basis of extensive spectroscopic analysis. All isolates were evaluated for their effects on nerve growth factor (NGF)-mediated neurite outgrowth in pheochromocytoma (PC12) cells. As a results, four compounds including 10-12 and 15 showed potent promoting effects at the concentration of 10 µM on NGF-induced neurite outgrowth in PC12 cells with the differentiation rate of 11.84%, 12.21%, 13.77% and 12.16%, respectively.


Assuntos
Fator de Crescimento Neural/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Raízes de Plantas/química , Rizoma/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Valeriana/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Fator de Crescimento Neural/metabolismo , Células PC12 , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Sesquiterpenos/química
19.
Life Sci ; 265: 118748, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33189827

RESUMO

AIMS: Radiotherapy has become a basic treatment modality for head and neck cancer. However, radiotherapy results in inevitable side effects, particularly radiation sialadenitis, that significantly impairs quality of life. A previous study indicated that nerve growth factor (NGF) has a radio-protective effect, but the mechanism was not determined in salivary glands. In this study, we explored the functional role and mechanism regarding how NGF protects salivary glands against IR-induced damage. MAIN METHODS: Human salivary gland (HSG) cells and C57BL/6 mice were selected to establish an IR-induced salivary gland damage model in vitro and in vivo. Recombinant NGF protein and NGF siRNA and over-expression plasmids were applied to manipulate NGF expression in vitro. AAV-NGF was retrogradely perfused into the submandibular gland (SMG) through the SMG duct to manipulate NGF expression in vitro. Small-molecule inhibitors and siRNAs were applied to inhibit AKT and JNK. Western blotting, quantitative PCR, flow cytometry and histology assays were performed to analyse the functional role and mechanism of NGF. KEY FINDINGS: Our study demonstrated that NGF expression was upregulated following radiotherapy both in human HSG cells and mouse SMG tissues. NGF could reduce IR-induced HSG cell apoptosis, and AAV-mediated gene therapy could restore the salivary flow rate and protect the salivary gland against IR-induced apoptosis in vivo. Mechanistically, NGF protects salivary glands from IR-induced apoptosis by de-phosphorylating JNK kinase rather than promoting AKT phosphorylation. SIGNIFICANCE: The current study findings indicated that the modulation of the NGF pathway might prevent IR-induced salivary hypo-function.


Assuntos
Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/farmacologia , Glândulas Salivares/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células , China , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Qualidade de Vida , Lesões Experimentais por Radiação/prevenção & controle , Radioterapia/efeitos adversos , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/metabolismo , Glândula Submandibular/patologia
20.
Toxicol Lett ; 338: 85-96, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309997

RESUMO

Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Fator de Crescimento Neural/farmacologia , Neuritos/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa/metabolismo , Neuritos/metabolismo , Neuritos/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Células PC12 , Ratos , Fatores de Tempo
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